The susceptibility of the developing nervous system to environmental agents has been a major concern with regard to children's health issues and has become of additional concern with the high level of exposure to children of toddler age and the increase in developmental disorders such as autism and schizophrenia. The formation and interactions between the various cell types in the brain are critically timed events and represent age windows of vulnerability for environmental exposure. One recent issue of concern is the impact of infection or a stimulation or alteration in the immune system during development (Harry and Kraft, 2012;Harry and Lein, 2011). One component of this response is the induction of interleukin-6 which has been linked to maternal infection and altered childhood outcomes. This cytokine has both pro- and anti-inflammatory properties but also plays a role as a growth factor. In previous work we demonstrated that tight regulation of this cytokine is critical for maintaining a normal glial response to chemical injury. Multiple studies have suggested that IL-6 is the critical determining factor for brain damage due to inflammation in development however, these studies utilized models of systemic infection or high levels of an inflammatory response. We have now demonstrated that direct exposure of the developing mouse brain to IL-6, in the absence of a full systemic immune response, can alter brain development with manifestation of an early onset of motoric ontogeny, potentially altering differentiation of oligodendroglia progenitors and produce long term changes in social behavior (Brunssen et al., 2012). These effects are very specific and do not replicate the pronounced behavioral alterations induced with a more severe and generalized inflammatory response. This work demonstrates a critical role for IL-6 in both brain development and in neuroprotective processes and provides a possible link between early developmental exposure to immune mediated events from environmental exposure and long-term alterations. 2.N-Butylbenzenesulfonamide (NBBS) is widely used as a plasticizer in polyacetals, polyamides, and polycarbonates and has been found in ground water and effluent from wastewater treatment sites. Limited studies in the literature report neurotoxicity of NBBS in rabbits and rats. When we exposed rats to NBBS (100, 200, or 300 mg/kg/d) via oral gavage (5 ml/kg bwt) daily/5 days/week for 27 days we did not observe changes in gait, locomotor activity, and rearing behavior. No histological lesions were observed in the testis, seminal vesicles, coagulating gland, epididymis, and prostate. Contrary to previous reports, there was no evidence of peripheral nerve lesions or gliosis in the hippocampus or cerebellum. mRNA levels for glial fibrillary acidic acid protein, interferon gamma, CXCR-3, intracellular adhesion molecule-1, and CD11b were not altered in the hippocampus while Iba-1 levels were decreased (Rider et al., 2012). 3. We have developed a model system to examine the progenitor cell population from the subgranular zone ofthe hippocampus at different ages and to determine if toxicant or drug exposure will alter these cells directly or alter the in vivo environment such that the ability of these progenitor cells to differentiate to mature functioning neurons is altered. We are using this model to identify novel signaling factors that can promote adult neurogenesis and improve brain repair and cognitive functioning. For these studies we continue to use a number of methods to examine alterations in the developing nervous system following exposure to environmental agents including immunohistochemistry and con-focal imaging, molecular techniques to examine mRNA level such as qRT-PCR, microarray, RNase protection assays, laser capture microdissection for isolation and enrichment of specific areas, neuroprogenitor cell cultures, adult derived neural stem/progenitor cells, as well as assessment of neurobehavioral functioning.

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Kraft, Andrew D; McPherson, Christopher A; Harry, G Jean (2016) Association Between Microglia, Inflammatory Factors, and Complement with Loss of Hippocampal Mossy Fiber Synapses Induced by Trimethyltin. Neurotox Res :
Szabo, Steven T; Harry, G Jean; Hayden, Kathleen M et al. (2016) Comparison of Metal Levels between Postmortem Brain and Ventricular Fluid in Alzheimer's Disease and Nondemented Elderly Controls. Toxicol Sci 150:292-300
Orihuela, Ruben; McPherson, Christopher A; Harry, Gaylia Jean (2016) Microglial M1/M2 polarization and metabolic states. Br J Pharmacol 173:649-65
Goulding, David R; White, Sally S; McBride, Sandra J et al. (2016) Gestational exposure to perfluorooctanoic acid (PFOA): Alterations in motor related behaviors. Neurotoxicology 58:110-119
Awada, Rana; Saulnier-Blache, Jean Sébastien; Grès, Sandra et al. (2014) Autotaxin downregulates LPS-induced microglia activation and pro-inflammatory cytokines production. J Cell Biochem 115:2123-32
Muessel, Michelle J; Harry, G Jean; Armstrong, David L et al. (2013) SDF-1α and LPA modulate microglia potassium channels through rho gtpases to regulate cell morphology. Glia 61:1620-8
Brunssen, Susan H; Moy, Sheryl S; Toews, Arrel D et al. (2013) Interleukin-6 (IL-6) receptor/IL-6 fusion protein (Hyper IL-6) effects on the neonatal mouse brain: possible role for IL-6 trans-signaling in brain development and functional neurobehavioral outcomes. Brain Behav Immun 27:42-53
Harry, G Jean (2013) Microglia during development and aging. Pharmacol Ther 139:313-26
Rao, Jagadeesh Sridhara; Kim, Hyung-Wook; Harry, Gaylia Jean et al. (2013) Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in the postmortem frontal cortex from schizophrenia patients. Schizophr Res 147:24-31
Rider, C V; Janardhan, K S; Rao, D et al. (2012) Evaluation of N-butylbenzenesulfonamide (NBBS) neurotoxicity in Sprague-Dawley male rats following 27-day oral exposure. Neurotoxicology 33:1528-35

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